TPPP/p25 in brain tumours: expression in non-neoplastic oligodendrocytes but not in oligodendroglioma cells

Preusser, Matthias; Lehotzky, Attila; Budka, Herbert; Ovádi, Judit; Kovács, Gábor

doi:10.1007/s00401-006-0173-6

Cited by 30 publications

(26 citation statements)

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“…The precentral gyrus of ALS patients exhibited no notable changes compared to normal controls (Figure 5a). In the brain tissue affected with oligodendroglioma, there was a lack of TPPP immunoreactivity (Figure 5b-d), consistent with a previous report [28].…”

Section: Distribution Of Tppp In Other Neurological Diseasessupporting

confidence: 91%

Relocation of p25¿/tubulin polymerization promoting protein from the nucleus to the perinuclear cytoplasm in the oligodendroglia of sporadic and COQ2 mutant multiple system atrophy

Ota

Obayashi

Ozaki

et al. 2014

Acta Neuropathologica Communications

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Abstractp25α/tubulin polymerization promoting protein (TPPP) is an oligodendroglial protein that plays crucial roles including myelination, and the stabilization of microtubules. In multiple system atrophy (MSA), TPPP is suggested to relocate from the myelin sheath to the oligodendroglial cell body, before the formation of glial cytoplasmic inclusions (GCIs), the pathologic hallmark of MSA. However, much is left unknown about the re-distribution of TPPP in MSA. We generated new antibodies against the N-and C-terminus of TPPP, and analyzed control and MSA brains, including the brain of a familial MSA patient carrying homozygous mutations in the coenzyme Q2 gene (COQ2). In control brain tissues, TPPP was localized not only in the cytoplasmic component of the oligodendroglia including perinuclear cytoplasm and peripheral processes in the white matter, but also in the nucleus of a fraction (62.4%) of oligodendroglial cells. Immunoelectron microscopic analysis showed TPPP in the nucleus and mitochondrial membrane of normal oligodendroglia, while western blot also supported its nuclear and mitochondrial existence. In MSA, the prevalence of nuclear TPPP was 48.6% in the oligodendroglia lacking GCIs, whereas it was further decreased to 19.6% in the oligodendroglia with phosphorylated α-synuclein (pα-syn)-positive GCIs, both showing a significant decrease compared to controls (62.4%). In contrast, TPPP accumulated in the perinuclear cytoplasm where mitochondrial membrane (TOM20 and cytochrome C) and fission (DRP1) proteins were often immunoreactive. We conclude that in MSA-oligodendroglia, TPPP is reduced, not only in the peripheral cytoplasm, but also in the nucleus and relocated to the perinuclear cytoplasm.

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Section: Distribution Of Tppp In Other Neurological Diseasessupporting

confidence: 91%

Relocation of p25¿/tubulin polymerization promoting protein from the nucleus to the perinuclear cytoplasm in the oligodendroglia of sporadic and COQ2 mutant multiple system atrophy

Ota

Obayashi

Ozaki

et al. 2014

Acta Neuropathologica Communications

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“…distinct CNS diseases such as glioma (brain tumor) [13], multiple sclerosis (demyelination) [14,15] or synucleinopathies (pathological inclusions) [16]. In fact, TPPP/p25 is able to induce α-synuclein (SYN) aggregation [17] in vitro; however, its overexpression and co-localization with SYN in human brain is a characteristic symptom of Parkinson's disease [16], thus we have suggested TPPP/p25 as a biomarker of synucleinopathies [16].…”

Section: U N C O R R E C T E D P R O O Fmentioning

confidence: 89%

“…For backbone assignment and structural characterization of human N-and C-terminal free TPPP/p25 protein 1D, 2D and 3D NMR experiments were carried out at 288 K such as 1 H-15 N-HSQC (8 transients collected using 118 ppm offset; 26 ppm spectral window and incremented in 512 points in the indirect dimension), 1 H-13 C-HSQC (16 transients with 40 ppm offset and 64 ppm spectral window incremented in 256 points in F1), HNCA, HNCOCA (for both indirect dimension: 8 transients with 50 ppm offset and 64 ppm window for 13 C and incremented in 64 × 128 points), HNCACB (16 transients collected with 40 ppm offset and 64 ppm spectral width for 13 C and incremented in 64 × 128 points), CCCONH (16 transients collected at 40 ppm offset with 64 ppm spectral window incremented in 64 × 128 points in the indirect dimensions).…”

Section: Multinuclear Nuclear Magnetic Resonance (Nmr)mentioning

confidence: 99%

Challenging drug target for Parkinson's disease: Pathological complex of the chameleon TPPP/p25 and alpha-synuclein proteins

Szénási¹,

Oláh²,

Szabó³

et al. 2017

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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The hallmarks of Parkinson's disease and other synucleinopathies, Tubulin Polymerization Promoting Protein (TPPP/p25) and α-synuclein (SYN) have two key features: they are disordered and co-enriched/co-localized in brain inclusions. These Neomorphic Moonlighting Proteins display both physiological and pathological functions due to their interactions with distinct partners. To achieve the selective targeting of the pathological TPPP/p25-SYN but not the physiological TPPP/ p25-tubulin complex, their interfaces were identified as a specific innovative strategy for the development of anti-Parkinson drugs. Therefore, the interactions of TPPP/p25 with tubulin and SYN were characterized which suggested the involvements of the 178-187 aa and 147-156 aa segments in the complexation of TPPP/p25 with tubulin and SYN, respectively. However, various truncated and deletion mutants reduced but did not abolish the interactions except one mutant; in addition synthetized fragments corresponding to the potential binding segments of TPPP/p25 failed to interact with SYN. In fact, the studies of the multiple interactions at molecular and cellular levels revealed the high conformational plasticity, chameleon feature, of TPPP/p25 that ensures exceptional functional resilience; the lack of previously identified binding segments could be replaced by other segments. The experimental results are underlined by distinct bioinformatics tools. All these data revealed that although targeting chameleon proteins is a challenging task, nevertheless, the validation of a drug target can be achieved by identifying the interface of complexes of the partner proteins existing at the given pathological conditions.

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“…Our results showed that the Zn 2+ -induced structural change can enhance the intracellular level of the disordered TPPP/p25 by counteracting its proteasomal degradation (Attila Lehotzky, Judit Oláh, Sándor Szunyogh, Adél Szabó, Tímea Berki, Judit Ovádi, submitted manuscript), which could be essential for the extension of projections playing role in the maintenance of the stability of the zinc-rich myelin sheath in the central nervous system (CNS). This is an important issue since both the enrichment and the lack of this protein leads to CNS diseases such as MSA [41] and glioma [42], respectively.…”

Section: Functions With Physiological Relevancementioning

confidence: 99%

“…The optimal intracellular expression of TPPP/p25 is a key factor for the physiology of the brain functions; the lack and enrichment of TPPP/p25 in oligodendrocytes lead to distinct CNS diseases: glioma [42] and MSA [41], respectively, (Fig. 3).…”

Section: Functions With Pathological Relevancementioning

confidence: 99%

Dual life of TPPP/p25 evolved in physiological and pathological conditions

Oláh

Ovádi

2014

Biochemical Society Transactions

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Neomorphic Moonlighting Proteins perform distinct functions at physiological and pathological conditions without alterations at gene level. The disordered Tubulin Polymerization Promoting Protein (TPPP/p25), a prototype of Neomorphic Moonlighting Proteins, modulates the dynamics and stability of the microtubule system via its bundling and tubulin acetylation promoting activities. These physiological functions are mediated by its direct associations with tubulin/microtubules as well as tubulin deacetylases such as HDAC6. In normal brain TPPP/p25 is expressed in oligodendrocytes and plays a crucial role in the formation of projections in the course of differentiation requested for axon ensheathment. At pathological conditions TPPP/p25 interacts with alpha-synuclein, forms aberrant protein-protein interaction resulting in aggregation leading to the formation of inclusions as clinical symptoms. The co-enrichment and co-localization of TPPP/p25 and alpha-synuclein were established in human brain inclusions characteristic for Parkinson's disease and other synucleinopathies. The binding segments on TPPP/p25 involved in the physiological and pathological interactions were identified and validated at molecular and cell levels using recombinant proteins and transfected HeLa and inducible CHO10 cells expressing TPPP/p25. Our finding that distinct motives are responsible for the neomorphic moonlighting feature of TPPP/p25 has powerful innovative impact in anti-Parkinson drug research. KEYWORDSTPPP/p25, tubulin, alpha-synuclein, moonlighting, acetylation, Parkinson's disease NEOMORPHIC MOONLIGHTING PROTEINSThe recognition that there are proteins with more than one function was recognized two decades ago and this characteristic was termed as moonlighting [1]. These proteins perform multiple, independent functions that are not coded at gene level, do not stem from genetic alterations (gene fusion or splice variants), their functions are manifested themselves at protein level. The functions of these moonlighting proteins can vary as a consequence of changes in cellular localization, cell type, and their oligomeric state, concentrations of substrates, cofactors or products [1]. In addition to these types of proteins, in which all functions are considered "normal", there are proteins displaying a second function that is not considered as a "normal" one [2]. These are Neomorphic Moonlighting Proteins, physiological function of which can be converted into a pathological one mostly due to their hetero-associations with "pathological" partners distinct from the physiological ones [2,3].The major part of the intracellular proteins has well-defined secondary and tertiary structures; however, a number of in silico and experimental data have been accumulated indicating that a part of proteins does not bear well-defined 3D structure [4][5][6]. These proteins denoted as intrinsically unstructured or disordered proteins, are rather common in living cells and fulfill essential physiological functions [4,5]. These functions are linked...

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TPPP/p25 in brain tumours: expression in non-neoplastic oligodendrocytes but not in oligodendroglioma cells

Cited by 30 publications

References 0 publications

Relocation of p25¿/tubulin polymerization promoting protein from the nucleus to the perinuclear cytoplasm in the oligodendroglia of sporadic and COQ2 mutant multiple system atrophy

Relocation of p25¿/tubulin polymerization promoting protein from the nucleus to the perinuclear cytoplasm in the oligodendroglia of sporadic and COQ2 mutant multiple system atrophy

Challenging drug target for Parkinson's disease: Pathological complex of the chameleon TPPP/p25 and alpha-synuclein proteins

Dual life of TPPP/p25 evolved in physiological and pathological conditions

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